Using DTI to assess white matter microstructure in cerebral small vessel disease (SVD) in multicentre studies

Iain D. Croall, Valerie Lohner, Barry Moynihan, Usman Khan, Ahamad Hassan, John T. O'Brien, Robin G. Morris, Daniel J. Tozer, Victoria C. Cambridge, Kirsty Harkness, David J. Werring, Andrew M. Blamire (+3 others)
2017 Clinical Science  
Diffusion tensor imaging (DTI) metrics such as fractional anisotropy (FA) and mean diffusivity (MD) have been proposed as clinical trial markers of cerebral small vessel disease (SVD) due to their associations with outcomes such as cognition. However, studies investigating this have been predominantly single-centre. As clinical trials are likely to be multisite, further studies are required to determine whether associations with cognition of similar strengths can be detected in a multicentre
more » ... ting. One hundred and nine patients (mean age =68 years) with symptomatic lacunar infarction and confluent white matter hyperintensities (WMH) on MRI was recruited across six sites as part of the PRESERVE DTI substudy. After handling missing data, 3T-MRI scanning was available from five sites on five scanner models (Siemens and Philips), alongside neuropsychological and quality of life (QoL) assessments. FA median and MD peak height were extracted from DTI histogram analysis. Multiple linear regressions were performed, including normalized brain volume, WMH lesion load, and n • lacunes as covariates, to investigate the association of FA and MD with cognition and QoL. DTI metrics from all white matter were significantly associated with global cognition (standardized β =0.268), mental flexibility (β =0.306), verbal fluency (β =0.376), and Montreal Cognitive Assessment (MoCA) (β =0.273). The magnitudes of these associations were comparable with those previously reported from single-centre studies found in a systematic literature review. In this multicentre study, we confirmed associations between DTI parameters and cognition, which were similar in strength to those found in previous single-centre studies. The present study supports the use of DTI metrics as biomarkers of disease progression in multicentre studies. Cognitive testing Assessment was performed by a neuropsychologist and occurred on the same day as MRI scanning or as close to the scan as possible. A cognitive test battery was used which included tests sensitive to the characteristic impairments in processing speed and executive function associated with SVD [2], with additional testing of memory. This included for Processing speed the Digit Symbol Coding test (DSC) [19] , and for executive functioning the Trail Making Test (TMT, [20] ) to measure mental flexibility and a phonemic verbal fluency task ("FAS") [21] and a semantic verbal fluency task (animals) [22] to measure verbal generativity.Memory was measured using the Rey Auditory Verbal Learning Test (RAVLT, [23]). Premorbid IQ was estimated using the restandardized National Adult Reading Test (NART-R, [24] ) and additional screening for cognitive impairment was conducted using the Montreal Cognitive Assessment (MoCA, [25] ). In addition, following assessments of disability and quality of life (QoL) were performed; the stroke-specific QoL assessment (SSQoL) [26] and the EuroQoL [27]. Performance across neuropsychological tests was made comparable by transforming raw scores into z-scores using the best available age-scaled normative data (DSC; [19], TMT; [28], letter fluency; [21], animal fluency; [22], RAVLT; [28]). Tasks were grouped into four key domains (Processing speed: Wechsler Adult Intelligence Scale coding total correct, TMT-A time to complete, Mental flexibility: TMT-B time to complete, Verbal fluency: total correct for 'FAS' letter fluency and animal fluency and Verbal memory: RAVLT 'immediate' and 'delayed' recall). Individual task z-scores were averaged across these groupings to create overall domain scores, while all domain scores were averaged to create a Global cognition domain. SSQoL (total score), EuroQoL ('healthstate' rating) and the MoCA (total score) were analysed individually using raw scores. Where data were missing due to a subject being unable to complete a task, the lowest available z-score was given; this applied to 15 individual tasks, across 13 participants (11.9% of the sample size). If data were missing for any other reasons then the domain scores were calculated without that task; this applied to three participants (2.8% of the sample size). • DTI metrics have been suggested as clinical trial markers of SVD, but studies investigating this have been single-centre and as clinical trials are likely to be multicentre. We investigate the associations between these metrics and cognition in a multicentre clinical trial of SVD. • In a cross-sectional analysis, significant associations were found between white matter DTI metrics and cognition; these were of a comparable magnitude with those previously reported in single-centre studies. • These findings support the use of DTI metrics as markers of SVD in multicentre clinical trials.
doi:10.1042/cs20170146 pmid:28487471 pmcid:PMC5461938 fatcat:u5qprq2xbvc7fa5uh7vue5rtcy